Abstract

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)⁺ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.

1. Laboratory of Genomic Diversity, Science Applications International Corporation–Frederick, Inc., National Cancer Institute, P.O. Box B, Building 560, Frederick, Maryland 21702, USA.
2. Laboratory of Experimental Immunology, National Cancer Institute, P.O. Box B, Building 560, Frederick, Maryland 21702, USA.
3. Department of Epidemiology and Biostatistics, University of California, 995 Potrero Avenue, San Francisco, California 94105, USA.
4. Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, 149 13^th Street, Boston, Massachusetts 02129, USA.
5. Institute of Microbiology, University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
6. Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 7066, Rockville, Maryland 20852, USA.
7. Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, 903 South Fourth Street, Hamilton, Montana 59840, USA.
8. Department of Medicine, Northwestern University Medical School, 676 North St. Clair, No. 200, Chicago, Illinois 60611, USA.
9. San Francisco Department of Public Health, HIV Research Section, 25 Van Ness Avenue, Suite 710, San Francisco, California 94102, USA.
10. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205, USA.
11. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 10 Center Drive, MSC 1876, Bethesda, Maryland 20892, USA.
12. Laboratory of Genomic Diversity, National Cancer Institute, P.O. Box B, Building 560, Frederick, Maryland 21702, USA.
13. Department of Structural Biology, Stanford University School of Medicine, Fairchild D-159, 299 Campus Drive West, Stanford, California 94305, USA.
14. San Francisco General Hospital, 995 Potrero Avenue, California 94110, USA.

Correspondence to: Mary Carrington¹ e-mail: carringt@ncifcrf.gov

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